Globally, infectious diseases cause over 13 million deaths each year, and cancers cause over 12 million deaths each year. For example, infection with Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide and can lead to pneumonia, meningitis and bacteraemia, and some less severe infections such as otitis media. Almost one million children in the developing world die of infections due to S. pneumoniae (more commonly known as pneumococcus) each year. Antibiotics offer effective treatment for many cases of pneumococcal disease. The rapid emergence of multiple-drug-resistant strains of S. pneumoniae, however, has limited the effectiveness of antibiotics and stimulated renewed interest in the prevention of pneumococcal infections with vaccines.
The success of passive immunization and polysaccharide-based vaccines for the prevention of colonization and/or disease has demonstrated the importance of capsular antibodies in controlling pneumococcal disease and colonization. Furthermore, studies in both animals and humans demonstrate that these antibodies can protect against nasopharyngeal (NP) pneumococcal colonization, which precedes pneumococcal disease. The importance of this effect has become clear and has paralleled what was learned after universal immunization with Haemophilus influenzae type b vaccine: in the U.S., the pneumococcal conjugate vaccine has prevented more than twice as many cases of invasive pneumococcal disease through indirect effects on pneumococcal transmission (i.e., herd immunity) as through its direct effect of protecting vaccinated children.
Protection by anticapsular antibody is limited by its serotype specificity: The 7-valent pneumococcal conjugate vaccine (PCV7) has significantly reduced the incidence of invasive pneumococcal disease due to vaccine-type (VT) strains. Recent studies have shown, however, that non-VT serotypes in PCV7 are gradually replacing VT, potentially limiting the usefulness of the vaccine. This has led to the evaluation of whether pneumococcal colonization can be prevented by immunization with conserved antigens. In particular, several pneumococcal proteins have been evaluated as vaccine candidates in animal models of pneumococcal colonization. Mucosal immunization with some of these proteins has been shown to elicit systemic and mucosal antibodies and to confer protection against pneumococcal disease and colonization. There remains a need for an immunogenic composition, including pneumococcal polysaccharides and proteins, that raises antibodies and a robust cellular and humoral immune response to all serotypes.
The innate immune response provides rapid and usually effective defense against microbial pathogens. This response involves recognition of pathogen-associated molecules, triggering production and release of inflammatory mediators, recruitment of leukocytes, and activation of antimicrobial effectors. The Toll-like receptors (TLRs), of which at least eleven have been described for mammals, are capable of discriminating among a wide variety of pathogen-associated molecules and eliciting protective responses. TLR4 recognizes microbial products from organisms including gram-negative bacteria, the F protein of respiratory syncytial virus, and cholesterol-dependent cytolysins (CDC) of gram-positive bacteria. Hence, there remains a need to harness the TLR4 mechanism in eliciting an immune response against infections such as pneumococcal colonization and disease.